Innate immunity is an essential defense system of vertebrates against invasion of pathogenic factors and, for example, Toll-like receptors (TLRs), retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), Nod-like receptors, cytosolic DNA receptors, cell surface C-type lectin receptors and the like play a major role. Of the above-mentioned receptors, TLRs are also known to have a role responsible for antitumor immunity, and clinical attempts to treat cancer patients are ongoing using BCG as TLR2/4 agonist, poly I:C as TLR3 agonist, monophosphoryl lipid A (MLA) as TLR4 agonist, Imiquimod (synthetic imidazoquinoline) as TLR7 agonist, SD-101 (phosphorothioate CpG ODN) as TLR9 agonist and the like.
On the other hand, the involvement of RLRs, from among the above-mentioned receptors, in the antitumor immunity has scarcely been reported; however, it has been reported that synthetic DNA could induce interferon independent apoptosis in human melanoma via RIG-I and MDA5 activation (non-patent document 1). The inventors have also reported that completely inactivated HVJ (hemagglutinating virus of Japan) has plural antitumor activities including antitumor immunity and induction of cancer cell-specific apoptosis (non-patent document 2), and found that virus-derived RNA fragments in HVJ-E are transduced via membrane fusion into the cytoplasm and recognized by RIG-I, and a virus-derived RNA/RIG-I complex activates transcription factors such as NF-κB, IRF-3, IRF-7 via a mitochondria antivirus signal protein (MAVS), activates pro-apoptotic molecules such as TRAIL and NOXA in human cancer cells, but does not activate those in non-cancer cells (non-patent documents 2, 3). The inventors have also found that HVJ-E transiently increases calcium in cytoplasm via membrane fusion and induces necroptosis of caspase8-deficient neuroblastoma cells (non-patent document 4). In addition, the inventors have reported that the function of regulatory T cell is suppressed independently of the membrane fusion by stimulating the production of IL-6 from dendritic cells via interaction of unidentified cell surface receptors on the dendritic cells with F protein of HVJ-E, thus contributing to the activation of antitumor immunity (non-patent documents 5, 6).
As mentioned above, the present inventors have demonstrated that HVJ-E can suppress proliferation of cancer cells by activating various signal transductions. However, it is still unknown how the proliferation suppressive effect of HVJ-E on cancer cells changes when signal transduction via TLRs is simultaneously activated.